WARNING: HEPATOTOXICITY and RISK OF TERATOGENICITY

Hepatotoxicity

Severe liver injury including fatal liver failure has been reported in patients treated with leflunomide, which is indicated for rheumatoid arthritis. A similar risk would be expected for teriflunomide because recommended doses of teriflunomide and leflunomide result in a similar range of plasma concentrations of teriflunomide. Concomitant use of AUBAGIO with other potentially hepatotoxic drugs may increase the risk of severe liver injury. Obtain transaminase and bilirubin levels within 6 months before initiation of AUBAGIO therapy. Monitor ALT levels at least monthly for six months after starting AUBAGIO [see Warnings and Precautions (5.1)]. If drug induced liver injury is suspected, discontinue AUBAGIO and start an accelerated elimination procedure with cholestyramine or charcoal [see Warnings and Precautions (5.3)]. AUBAGIO is contraindicated in patients with severe hepatic impairment [see Contraindications (4)]. Patients with pre-existing liver disease may be at increased risk of developing elevated serum transaminases when taking AUBAGIO.

Risk of Teratogenicity

AUBAGIO is contraindicated for use in pregnant women and in women of reproductive potential who are not using effective contraception because of the potential for fetal harm. Teratogenicity and embryolethality occurred in animals at plasma teriflunomide exposures lower than that in humans. Exclude pregnancy before the start of treatment with AUBAGIO in females of reproductive potential. Advise females of reproductive potential to use effective contraception during AUBAGIO treatment and during an accelerated drug elimination procedure after AUBAGIO treatment. Stop AUBAGIO and use an accelerated drug elimination procedure if the patient becomes pregnant [see Contraindications (4), Warnings and Precautions (5.2, 5.3), Use in Specific Populations (8.1), and Clinical Pharmacology (12.3)].

These highlights do not include all the information needed to use AUBAGIO
® safely and effectively. See full prescribing information for AUBAGIO.

AUBAGIO (teriflunomide) tablets, for oral use
Initial U.S. Approval: 2012

WARNING: HEPATOTOXICITY and RISK OF TERATOGENICITY

See full prescribing information for complete boxed warning

Hepatotoxicity

Severe liver injury including fatal liver failure has been reported in patients treated with leflunomide, which is indicated for rheumatoid arthritis. A similar risk would be expected for teriflunomide because recommended doses of teriflunomide and leflunomide result in a similar range of plasma concentrations of teriflunomide. Obtain transaminase and bilirubin levels within 6 months before initiation of AUBAGIO and monitor ALT levels at least monthly for six months (5.1). If drug induced liver injury is suspected, discontinue AUBAGIO and start accelerated elimination procedure (5.3).

DOSAGE FORMS AND STRENGTHS

CONTRAINDICATIONS

WARNINGS AND PRECAUTIONS

Elimination of AUBAGIO can be accelerated by administration of cholestyramine or activated charcoal for 11 days (5.3)

AUBAGIO may decrease WBC. A recent CBC should be available before starting AUBAGIO. Monitor for signs and symptoms of infection. Consider suspending treatment with AUBAGIO in case of serious infection. Do not start AUBAGIO in patients with active infections (5.4)

The recommended dose of AUBAGIO is 7 mg or 14 mg orally once daily. AUBAGIO can be taken with or without food.

Monitoring to assess safety

Obtain transaminase and bilirubin levels within 6 months before initiation of AUBAGIO therapy. Monitor ALT levels at least monthly for six months after starting AUBAGIO [see Warnings and Precautions (5.1)].

Obtain a complete blood cell count (CBC) within 6 months before the initiation of treatment with AUBAGIO. Further monitoring should be based on signs and symptoms of infection [see Warnings and Precautions (5.4)].

The 14 mg tablet is a pale blue to pastel blue, pentagonal film-coated tablet with the dose strength, "14" imprinted on one side and engraved with the corporate logo on the other side. Each tablet contains 14 mg of teriflunomide.

The 7 mg tablet is a very light greenish-bluish grey to pale greenish-blue, hexagonal film-coated tablet with dose strength "7" imprinted on one side and engraved with the corporate logo on other side. Each tablet contains 7 mg of teriflunomide.

Patients with a history of a hypersensitivity reaction to teriflunomide, leflunomide, or to any of the inactive ingredients in AUBAGIO. Reactions have included anaphylaxis, angioedema, and serious skin reactions [see Warnings and Precautions (5.5)].

5.1 Hepatotoxicity

Severe liver injury including fatal liver failure and dysfunction has been reported in some patients treated with leflunomide, which is indicated for rheumatoid arthritis. A similar risk would be expected for teriflunomide because recommended doses of teriflunomide and leflunomide result in a similar range of plasma concentrations of teriflunomide. Patients with pre-existing liver disease may be at increased risk of developing elevated serum transaminases when taking AUBAGIO. Patients with pre-existing acute or chronic liver disease, or those with serum alanine aminotransferase (ALT) greater than two times the upper limit of normal (ULN) before initiating treatment, should not normally be treated with AUBAGIO. AUBAGIO is contraindicated in patients with severe hepatic impairment [see Contraindications (4)].

In placebo-controlled trials, ALT greater than three times the ULN occurred in 61/1045 (5.8%) and 62/1002 (6.2%) of patients receiving AUBAGIO 7 mg and 14 mg, respectively, and 38/997 (3.8%) of patients receiving placebo, during the treatment period. These elevations occurred mostly within the first year of treatment. Half of the cases returned to normal without drug discontinuation. In clinical trials, if ALT elevation was greater than three times the ULN on two consecutive tests, AUBAGIO was discontinued and patients underwent an accelerated elimination procedure [see Warnings and Precautions (5.3)]. Of the patients who underwent discontinuation and accelerated elimination in controlled trials, half returned to normal or near normal values within 2 months.

One patient in the controlled trials developed ALT 32 times the ULN and jaundice 5 months after initiation of AUBAGIO 14 mg treatment. The patient was hospitalized for 5 weeks and recovered after plasmapheresis and cholestyramine accelerated elimination procedure. AUBAGIO-induced liver injury in this patient could not be ruled out.

Obtain serum transaminase and bilirubin levels within 6 months before initiation of AUBAGIO therapy. Monitor ALT levels at least monthly for six months after starting AUBAGIO. Consider additional monitoring when AUBAGIO is given with other potentially hepatotoxic drugs.

Consider discontinuing AUBAGIO if serum transaminase increase (greater than three times the ULN) is confirmed. Monitor serum transaminase and bilirubin on AUBAGIO therapy, particularly in patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine. If liver injury is suspected to be AUBAGIO-induced, discontinue AUBAGIO and start an accelerated elimination procedure [see Warnings and Precautions (5.3)] and monitor liver tests weekly until normalized. If AUBAGIO-induced liver injury is unlikely because some other probable cause has been found, resumption of AUBAGIO therapy may be considered.

5.2 Teratogenicity

AUBAGIO may cause fetal harm when administered to a pregnant woman. Teratogenicity and embryo-fetal lethality occurred in animal reproduction studies in multiple animal species at plasma teriflunomide exposures similar to or lower than that in humans at the maximum human recommended dose (MHRD) of 14 mg/day [see Use in Specific Populations (8.1)].

5.3 Procedure for Accelerated Elimination of Teriflunomide

Teriflunomide is eliminated slowly from the plasma [see Clinical Pharmacology (12.3)]. Without an accelerated elimination procedure, it takes on average 8 months to reach plasma concentrations less than 0.02 mg/L, although because of individual variations in drug clearance it may take as long as 2 years. An accelerated elimination procedure could be used at any time after discontinuation of AUBAGIO. Elimination can be accelerated by either of the following procedures:

Administration of cholestyramine 8 g every 8 hours for 11 days. If cholestyramine 8 g three times a day is not well tolerated, cholestyramine 4 g three times a day can be used.

If either elimination procedure is poorly tolerated, treatment days do not need to be consecutive unless there is a need to lower teriflunomide plasma concentration rapidly.

At the end of 11 days, both regimens successfully accelerated teriflunomide elimination, leading to more than 98% decrease in teriflunomide plasma concentrations.

Use of the accelerated elimination procedure may potentially result in return of disease activity if the patient had been responding to AUBAGIO treatment.

5.4 Bone Marrow Effects/Immunosuppression Potential/Infections

Bone Marrow Effects

A mean decrease compared to baseline in white blood cell (WBC) count of approximately 15% (mainly neutrophils and lymphocytes) and in platelet count of approximately 10% was observed in placebo-controlled trials with 7 mg and 14 mg of AUBAGIO. The decrease in mean WBC count occurred during the first 6 weeks and WBC count remained low during treatment. In placebo-controlled studies, neutrophil count <1.5×109/L was observed in 12% and 16% of patients receiving AUBAGIO 7 mg and 14 mg, respectively, compared with 7% of patients receiving placebo; lymphocyte count <0.8× 109/L was observed in 10% and 12% of patients receiving AUBAGIO 7 mg and 14 mg, respectively, compared with 6% of patients receiving placebo. No cases of serious pancytopenia were reported in premarketing clinical trials of AUBAGIO but rare cases of pancytopenia and agranulocytosis have been reported in the postmarketing setting with leflunomide. A similar risk would be expected for AUBAGIO [see Clinical Pharmacology (12.3)]. Cases of thrombocytopenia with AUBAGIO, including rare cases with platelet counts less than 50,000/mm3, have been reported in the postmarketing setting. Obtain a complete blood cell count (CBC) within 6 months before the initiation of treatment with AUBAGIO. Further monitoring should be based on signs and symptoms suggestive of bone marrow suppression.

Risk of Infection / Tuberculosis Screening

Patients with active acute or chronic infections should not start treatment until the infection(s) is resolved. If a patient develops a serious infection consider suspending treatment with AUBAGIO and using an accelerated elimination procedure. Reassess the benefits and risks prior to resumption of therapy. Instruct patients receiving AUBAGIO to report symptoms of infections to a physician.

AUBAGIO is not recommended for patients with severe immunodeficiency, bone marrow disease, or severe, uncontrolled infections. Medications like AUBAGIO that have immunosuppression potential may cause patients to be more susceptible to infections, including opportunistic infections.

In placebo-controlled studies of AUBAGIO, no overall increase in the risk of serious infections was observed with AUBAGIO 7 mg (2.2%) or 14 mg (2.7%) compared to placebo (2.2%).

However, one fatal case of klebsiella pneumonia sepsis occurred in a patient taking AUBAGIO 14 mg for 1.7 years. Fatal infections have been reported in the postmarketing setting in patients receiving leflunomide, especially Pneumocystis jiroveci pneumonia and aspergillosis. Most of the reports were confounded by concomitant immunosuppressant therapy and/or comorbid illness which, in addition to rheumatoid disease, may predispose patients to infection. In clinical studies with AUBAGIO, cytomegalovirus hepatitis reactivation has been observed.

In clinical studies with AUBAGIO, cases of tuberculosis have been observed. Prior to initiating AUBAGIO, screen patients for latent tuberculosis infection with a tuberculin skin test or with a blood test for mycobacterium tuberculosis infection. AUBAGIO has not been studied in patients with a positive tuberculosis screen, and the safety of AUBAGIO in individuals with latent tuberculosis infection is unknown. For patients testing positive in tuberculosis screening, treat by standard medical practice prior to therapy with AUBAGIO.

Vaccination

No clinical data are available on the efficacy and safety of live vaccinations in patients taking AUBAGIO. Vaccination with live vaccines is not recommended. The long half-life of AUBAGIO should be considered when contemplating administration of a live vaccine after stopping AUBAGIO.

Malignancy

The risk of malignancy, particularly lymphoproliferative disorders, is increased with the use of some immunosuppressive medications. There is a potential for immunosuppression with AUBAGIO. No apparent increase in the incidence of malignancies and lymphoproliferative disorders was reported in the AUBAGIO clinical trials, but larger and longer-term studies would be needed to determine whether there is an increased risk of malignancy or lymphoproliferative disorders with AUBAGIO.

5.5 Hypersensitivity and Serious Skin Reactions

AUBAGIO can cause anaphylaxis and severe allergic reactions [see Contraindications (4)]. Signs and symptoms have included dyspnea, urticaria, and angioedema including lips, eyes, throat, and tongue.

Cases of serious skin reactions, including cases of Stevens-Johnson syndrome (SJS) and a fatal case of toxic epidermal necrolysis (TEN), have been reported with AUBAGIO.

In patients treated with leflunomide, the parent compound, very rare cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) have also been reported.

Inform patients of the signs and symptoms of anaphylaxis and angioedema and signs and symptoms that may signal a serious skin reaction. Inform patients that a fever associated with signs of other organ system involvement (e.g., rash, lymphadenopathy, or hepatic dysfunction) may be drug-related. Instruct patients to discontinue AUBAGIO and seek immediate medical care should these signs and symptoms occur. Discontinue AUBAGIO, unless the reactions are clearly not drug-related, and begin an accelerated elimination procedure immediately [see Warnings and Precautions (5.3)]. In such cases, patients should not be re-exposed to teriflunomide [see Contraindications (4)].

Age older than 60 years, concomitant neurotoxic medications, and diabetes may increase the risk for peripheral neuropathy. If a patient taking AUBAGIO develops symptoms consistent with peripheral neuropathy, such as bilateral numbness or tingling of hands or feet, consider discontinuing AUBAGIO therapy and performing an accelerated elimination procedure [see Warnings and Precautions (5.3)].

5.7 Increased Blood Pressure

In placebo-controlled studies, the mean change from baseline to the end of study in systolic blood pressure was +2.3 mmHg and +2.7 mmHg for AUBAGIO 7 mg and 14 mg, respectively, and -0.6 mmHg for placebo. The change from baseline in diastolic blood pressure was +1.4 mmHg and +1.9 mmHg for AUBAGIO 7 mg and 14 mg, respectively, and -0.3 mmHg for placebo. Hypertension was an adverse reaction in 3.1% and 4.3% of patients treated with 7 mg or 14 mg of AUBAGIO compared with 1.8% for placebo. Check blood pressure before start of AUBAGIO treatment and periodically thereafter. Elevated blood pressure should be appropriately managed during treatment with AUBAGIO.

5.8 Respiratory Effects

Interstitial lung disease, including acute interstitial pneumonitis, has been reported with AUBAGIO in the postmarketing setting.

Interstitial lung disease and worsening of pre-existing interstitial lung disease have been reported during treatment with leflunomide. Interstitial lung disease may be fatal and may occur acutely at any time during therapy with a variable clinical presentation. New onset or worsening pulmonary symptoms, such as cough and dyspnea, with or without associated fever, may be a reason for discontinuation of therapy and for further investigation as appropriate. If discontinuation of the drug is necessary, consider initiation of an accelerated elimination procedure [see Warnings and Precautions (5.3)].

5.9 Concomitant Use with Immunosuppressive or Immunomodulating Therapies

Coadministration with antineoplastic, or immunosuppressive therapies used for treatment of multiple sclerosis has not been evaluated. Safety studies in which AUBAGIO was concomitantly administered with other immune modulating therapies for up to one year (interferon beta, glatiramer acetate) did not reveal any specific safety concerns. The long term safety of these combinations in the treatment of multiple sclerosis has not been established.

In any situation in which the decision is made to switch from AUBAGIO to another agent with a known potential for hematologic suppression, it would be prudent to monitor for hematologic toxicity, because there will be overlap of systemic exposure to both compounds. Use of an accelerated elimination procedure may decrease this risk, but may also potentially result in return of disease activity if the patient had been responding to AUBAGIO treatment [see Warnings and Precautions (5.3)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

A total of 2047 patients receiving AUBAGIO (7 mg or 14 mg once daily) constituted the safety population in the pooled analysis of placebo controlled studies in patients with relapsing forms of multiple sclerosis; of these, 71% were female. The average age was 37 years.

Table 1 lists adverse reactions in placebo-controlled trials with rates that were at least 2% for AUBAGIO patients and also at least 2% above the rate in placebo patients. The most common were headache, an increase in ALT, diarrhea, alopecia, and nausea. The adverse reaction most commonly associated with discontinuation was an increase in ALT (3.3%, 2.6%, and 2.3% of all patients in the AUBAGIO 7 mg, AUBAGIO 14 mg, and placebo treatment arms, respectively).

Four cardiovascular deaths, including three sudden deaths, and one myocardial infarction in a patient with a history of hyperlipidemia and hypertension were reported among approximately 2600 patients exposed to AUBAGIO in the premarketing database. These cardiovascular deaths occurred during uncontrolled extension studies, one to nine years after initiation of treatment. A relationship between AUBAGIO and cardiovascular death has not been established.

Acute Renal Failure

In placebo-controlled studies, creatinine values increased more than 100% over baseline in 8/1045 (0.8%) patients in the 7 mg AUBAGIO group and 6/1002 (0.6%) patients in the 14 mg AUBAGIO group versus 4/997 (0.4%) patients in the placebo group. These elevations were transient. Some elevations were accompanied by hyperkalemia. AUBAGIO may cause acute uric acid nephropathy with transient acute renal failure because AUBAGIO increases renal uric acid clearance.

Hypophosphatemia

In clinical trials, 18% of AUBAGIO-treated patients had hypophosphatemia with serum phosphorus levels of at least 0.6 mmol/L, compared to 7% of placebo-treated patients; 4% of AUBAGIO-treated patients had hypophosphatemia with serum phosphorus levels at least 0.3 mmol/L but less than 0.6 mmol/L, compared to 0.8% of placebo-treated patients. No patient in any treatment group had a serum phosphorus below 0.3 mmol/L.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of AUBAGIO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Teriflunomide is an inhibitor of CYP2C8 in vivo. In patients taking AUBAGIO, exposure of drugs metabolized by CYP2C8 (e.g., paclitaxel, pioglitazone, repaglinide, rosiglitazone) may be increased. Monitor these patients and adjust the dose of the concomitant drug(s) metabolized by CYP2C8 as required [see Clinical Pharmacology (12.3)].

Effect of AUBAGIO on warfarin

Coadministration of AUBAGIO with warfarin requires close monitoring of the international normalized ratio (INR) because AUBAGIO may decrease peak INR by approximately 25%.

Effect of AUBAGIO on oral contraceptives

AUBAGIO may increase the systemic exposures of ethinylestradiol and levonorgestrel. Consideration should be given to the type or dose of contraceptives used in combination with AUBAGIO [see Clinical Pharmacology (12.3)].

Effect of AUBAGIO on CYP1A2 substrates

Teriflunomide may be a weak inducer of CYP1A2 in vivo. In patients taking AUBAGIO, exposure of drugs metabolized by CYP1A2 (e.g., alosetron, duloxetine, theophylline, tizanidine) may be reduced. Monitor these patients and adjust the dose of the concomitant drug(s) metabolized by CYP1A2 as required [see Clinical Pharmacology (12.3)].

Effect of AUBAGIO on organic anion transporter 3 (OAT3) substrates

Teriflunomide inhibits the activity of OAT3 in vivo. In patients taking AUBAGIO, exposure of drugs which are OAT3 substrates (e.g., cefaclor, cimetidine, ciprofloxacin, penicillin G, ketoprofen, furosemide, methotrexate, zidovudine) may be increased. Monitor these patients and adjust the dose of the concomitant drug(s) which are OAT3 substrates as required [see Clinical Pharmacology (12.3)].

Teriflunomide inhibits the activity of BCRP and OATP1B1/1B3 in vivo. For a patient taking AUBAGIO, the dose of rosuvastatin should not exceed 10 mg once daily. For other substrates of BCRP (e.g., mitoxantrone) and drugs in the OATP family (e.g., methotrexate, rifampin), especially HMG-Co reductase inhibitors (e.g., atorvastatin, nateglinide, pravastatin, repaglinide, and simvastatin), consider reducing the dose of these drugs and monitor patients closely for signs and symptoms of increased exposures to the drugs while patients are taking AUBAGIO [see Clinical Pharmacology (12.3)].

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AUBAGIO during pregnancy. Healthcare providers and patients are encouraged to report pregnancies by calling 1-800-745-4447, option 2

Risk Summary

AUBAGIO is contraindicated for use in pregnant women and females of reproductive potential not using effective contraception because of the potential for fetal harm based on animal data. Human data are not available at this time to inform the presence or absence of drug-associated risk with the use of AUBAGIO during pregnancy.

In animal reproduction studies in rat and rabbits, oral administration of teriflunomide during organogenesis caused teratogenicity and embryolethality at plasma exposures (AUC) lower than that at the maximum human recommended dose (MHRD) of 14 mg/day [see Data].

In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%–4% and 15%–20%, respectively. The background risk of major birth defects and miscarriage in the indicated population is unknown.

Clinical Considerations

Women who wish to become pregnant should discontinue use of AUBAGIO and undergo an accelerated elimination procedure to decrease the plasma concentration of teriflunomide to less than 0.02 mg/L (0.02 mcg/mL). Effective contraception should be used until is it verified that plasma concentrations of teriflunomide are less than 0.02 mg/L (0.02 mcg/mL) [see Warnings and Precautions (5.3)]. Human plasma concentrations of teriflunomide less than 0.02 mg/L (0.02 mcg/mL) are expected to have minimal embryofetal risk [see Contraindications (4) and Warnings and Precautions (5.3)].

If the patient becomes pregnant while taking this drug, stop treatment with AUBAGIO, inform the patient of the potential risk to the fetus, and perform the accelerated drug elimination procedure to achieve plasma concentrations of less than 0.02 mg/L (0.02 mcg/mL) [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)]. Refer the patient to an obstetrician/gynecologist, preferably experienced in reproductive toxicity, for further evaluation and counseling [see Warnings and Precautions (5.2, 5.3)].

Data

Animal Data

When teriflunomide (oral doses of 1, 3, or 10 mg/kg/day) was administered to pregnant rats throughout the period of organogenesis, high incidences of fetal malformation (primarily craniofacial, and axial and appendicular skeletal defects) and embryofetal death were observed at doses not associated with maternal toxicity. Adverse effects on embryofetal development were observed following dosing at various stages throughout organogenesis. Maternal plasma exposure at the no-effect level (1.0 mg/kg/day) for embryofetal developmental toxicity in rats was less than that in humans at the maximum recommended human dose (MRHD, 14 mg /day).

Administration of teriflunomide (oral doses of 1, 3.5, or 12 mg/kg/day) to pregnant rabbits throughout organogenesis resulted in high incidences of fetal malformation (primarily craniofacial, and axial and appendicular skeletal defects) and embryofetal death at doses associated with minimal maternal toxicity. Maternal plasma exposure at the no-effect dose (1.0 mg/kg/day) for embryofetal developmental toxicity in rabbits was less than that in humans at the MRHD.

In studies in which teriflunomide (oral doses of 0.05, 0.1, 0.3, 0.6, or 1.0 mg/kg/day) was administered to rats during gestation and lactation, decreased growth, eye and skin abnormalities, and high incidences of malformation (limb defects) and postnatal death were observed in the offspring at doses not associated with maternal toxicity. Maternal plasma exposure at the no-effect dose for pre- and postnatal developmental toxicity in rats (0.10 mg/kg/day) was less than that in humans at the MRHD.

In animal reproduction studies of leflunomide, embryolethality and teratogenic effects were observed in pregnant rat and rabbit at or below clinically relevant plasma teriflunomide exposures (AUC). In published reproduction studies in pregnant mice, leflunomide was embryolethal and increased the incidence of malformations (craniofacial, axial skeletal, heart and great vessel). Supplementation with exogenous uridine reduced the teratogenic effects in pregnant mice, suggesting that the mode of action (inhibition of mitochondrial enzyme dihydroorotate dehydrogenase) is the same for therapeutic efficacy and developmental toxicity. At recommended doses in humans, teriflunomide and leflunomide result in a similar range of plasma concentrations of teriflunomide.

8.2 Lactation

Risk Summary

It is not known whether this drug is excreted in human milk. Teriflunomide was detected in rat milk following a single oral dose.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for AUBAGIO and any potential adverse effects on the breastfed infant from AUBAGIO or from the underlying maternal condition.

Females of reproductive potential should use effective contraception while taking AUBAGIO. If AUBAGIO is discontinued, use of contraception should be continued until is it verified that plasma concentrations of teriflunomide are less than 0.02 mg/L (0.02 mcg/mL).

Females of reproductive potential who wish to become pregnant should undergo an accelerated elimination procedure. Effective contraception should be used until it is verified that plasma concentrations of teriflunomide are less than 0.02 mg/L (0.02 mcg/mL) [see Warnings and Precautions (5.3)].

Males

AUBAGIO is detected in human semen. Animal studies to specifically evaluate the risk of male-mediated fetal toxicity have not been conducted. To minimize any possible risk, men not wishing to father a child and their female partners should use effective contraception. Men wishing to father a child should discontinue use of AUBAGIO and either undergo an accelerated elimination procedure or wait until verification that the plasma teriflunomide concentration is less than 0.02 mg/L (0.02 mcg/mL) [see Warnings and Precautions (5.3)].

Infertility

Administration of teriflunomide to male rats resulted in no adverse effects on fertility. However, reduced epididymal sperm count was observed [see Nonclinical Toxicology (13.1)]. Effects of AUBAGIO on fertility in humans have not been evaluated.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of AUBAGIO did not include patients over 65 years old.

AUBAGIO (teriflunomide) is an oral de novo pyrimidine synthesis inhibitor of the DHO-DH enzyme, with the chemical name (Z)-2-Cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethylphenyl)-amide. Its molecular weight is 270.21, and the empirical formula is C12H9F3N2O2 with the following chemical structure:

Teriflunomide is a white to almost white powder that is sparingly soluble in acetone, slightly soluble in polyethylene glycol and ethanol, very slightly soluble in isopropanol and practically insoluble in water.

Teriflunomide is formulated as film-coated tablets for oral administration. AUBAGIO tablets contain 7 mg or 14 mg of teriflunomide and the following inactive ingredients: lactose monohydrate, corn starch, hydroxypropylcellulose, microcrystalline cellulose, sodium starch glycolate, and magnesium stearate. The film coating for the 14 mg tablet is made of hypromellose, titanium dioxide, talc, polyethylene glycol and indigo carmine aluminum lake. In addition to these, the 7 mg tablet film coating includes iron oxide yellow.

12.1 Mechanism of Action

Teriflunomide, an immunomodulatory agent with anti-inflammatory properties, inhibits dihydroorotate dehydrogenase, a mitochondrial enzyme involved in de novo pyrimidine synthesis. The exact mechanism by which teriflunomide exerts its therapeutic effect in multiple sclerosis is unknown but may involve a reduction in the number of activated lymphocytes in CNS.

12.2 Pharmacodynamics

Potential to prolong the QT interval

In a placebo controlled thorough QT study performed in healthy subjects, there was no evidence that teriflunomide caused QT interval prolongation of clinical significance (i.e., the upper bound of the 90% confidence interval for the largest placebo-adjusted, baseline-corrected QTc was below 10 ms).

12.3 Pharmacokinetics

Teriflunomide is the principal active metabolite of leflunomide and is responsible for leflunomide's activity in vivo. At recommended doses, teriflunomide and leflunomide result in a similar range of plasma concentrations of teriflunomide.

Based on a population analysis of teriflunomide in healthy volunteers and MS patients, median t1/2 was approximately 18 and 19 days after repeated doses of 7 mg and 14 mg respectively. It takes approximately 3 months respectively to reach steady-state concentrations. The estimated AUC accumulation ratio is approximately 30 after repeated doses of 7 or 14 mg.

Absorption

Median time to reach maximum plasma concentrations is between 1 to 4 hours post dose following oral administration of teriflunomide.

Food does not have a clinically relevant effect on teriflunomide pharmacokinetics.

Distribution

Teriflunomide is extensively bound to plasma protein (>99%) and is mainly distributed in plasma. The volume of distribution is 11 L after a single intravenous (IV) administration.

Metabolism

Teriflunomide is the major circulating moiety detected in plasma. The primary biotransformation pathway to minor metabolites of teriflunomide is hydrolysis, with oxidation being a minor pathway. Secondary pathways involve oxidation, N-acetylation and sulfate conjugation.

Elimination

Teriflunomide is eliminated mainly through direct biliary excretion of unchanged drug as well as renal excretion of metabolites. Over 21 days, 60.1% of the administered dose is excreted via feces (37.5%) and urine (22.6%). After an accelerated elimination procedure with cholestyramine, an additional 23.1% was recovered (mostly in feces). After a single IV administration, the total body clearance of teriflunomide is 30.5 mL/h.

Drug Interaction Studies

Teriflunomide is not metabolized by Cytochrome P450 or flavin monoamine oxidase enzymes.

The Potential Effect of AUBAGIO on Other Drugs

CYP2C8 SubstratesThere was an increase in mean repaglinide Cmax and AUC (1.7- and 2.4-fold, respectively) following repeated doses of teriflunomide and a single dose of 0.25 mg repaglinide, suggesting that teriflunomide is an inhibitor of CYP2C8 in vivo. The magnitude of interaction could be higher at the recommended repaglinide dose [see Drug Interactions (7)].

CYP1A2 SubstratesRepeated doses of teriflunomide decreased mean Cmax and AUC of caffeine by 18% and 55%, respectively, suggesting that teriflunomide may be a weak inducer of CYP1A2 in vivo [see Drug Interactions (7)].

OAT3 SubstratesThere was an increase in mean cefaclor Cmax and AUC (1.43- and 1.54-fold, respectively), following repeated doses of teriflunomide, suggesting that teriflunomide is an inhibitor of organic anion transporter 3 (OAT3) in vivo [see Drug Interactions (7)].

BCRP and OATP1B1/1B3 SubstratesThere was an increase in mean rosuvastatin Cmax and AUC (2.65- and 2.51-fold, respectively) following repeated doses of teriflunomide , suggesting that teriflunomide is an inhibitor of BCRP transporter and organic anion transporting polypeptide 1B1 and 1B3 (OATP1B1/1B3) [see Drug Interactions (7)].

Oral ContraceptivesThere was an increase in mean ethinylestradiol Cmax and AUC0–24 (1.58- and 1.54-fold, respectively) and levonorgestrel Cmax and AUC0–24 (1.33- and 1.41-fold, respectively) following repeated doses of teriflunomide [see Drug Interactions (7)].

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

No evidence of carcinogenicity was observed in lifetime carcinogenicity bioassays in mouse and rat. In mouse, teriflunomide was administered orally at doses up to 12 mg/kg/day for up to 95–104 weeks; plasma teriflunomide exposures (AUC) at the highest dose tested are approximately 3 times that in humans at the maximum recommended human dose (MRHD, 14 mg/day). In rat, teriflunomide was administered orally at doses up to 4 mg/kg/day for up to 97–104 weeks; plasma teriflunomide AUCs at the highest doses tested are less than that in humans at the MRHD.

Mutagenesis

Teriflunomide was negative in the in vitro bacterial reverse mutation (Ames) assay, the in vitro HPRT assay, and in in vivo micronucleus and chromosomal aberration assays. Teriflunomide was positive in an in vitro chromosomal aberration assay in human lymphocytes, with and without metabolic activation. Addition of uridine (to supplement the pyrimidine pool) reduced the magnitude of the clastogenic effect; however, teriflunomide was positive in the in vitro chromosomal aberration assay, even in the presence of uridine.

4-Trifluoromethylaniline (4-TFMA), a minor metabolite of teriflunomide, was positive in the in vitro bacterial reverse mutation (Ames) assay, the in vitro HPRT assay, and the in vitro chromosomal aberration assay in mammalian cells. 4-TFMA was negative in in vivo micronucleus and chromosomal aberration assays.

Impairment of fertility

Oral administration of teriflunomide (0, 1, 3, 10 mg/kg/day) to male rats prior to and during mating (to untreated females) resulted in no adverse effects on fertility; however, reduced epididymal sperm count was observed at the mid and high doses tested. The no-effect dose for reproductive toxicity in male rats (1 mg/kg) is less than the MRHD on a mg/m2 basis.

Oral administration of teriflunomide (0, 0.84, 2.6, 8.6 mg/kg/day) to female rats, prior to and during mating (to untreated males) and continuing to gestation day 6, resulted in embryolethality, reduced fetal body weight, and/or malformations at all doses tested. Due to marked embryolethality at the highest dose tested, no fetuses were available for evaluation. The lowest dose tested is less than the MRHD on a mg/m2 basis.

Four randomized, controlled, double-blind clinical trials established the efficacy of AUBAGIO in patients with relapsing forms of multiple sclerosis.

Study 1 was a double-blind, placebo-controlled clinical trial that evaluated once daily doses of AUBAGIO 7 mg and AUBAGIO 14 mg for up to 26 months in patients with relapsing forms of multiple sclerosis. Patients were required to have a diagnosis of multiple sclerosis exhibiting a relapsing clinical course, with or without progression, and to have experienced at least one relapse over the year preceding the trial or at least two relapses over the two years preceding the trial. Patients were required not to have received interferon-beta for at least four months, or any other multiple sclerosis medication for at least six months before entering the study, nor were these medications permitted during the study. Neurological evaluations were to be performed at screening, every 12 weeks until week 108, and after suspected relapses. MRI was to be performed at screening, and at Week 24, 48, 72, and 108. The primary endpoint was the annualized relapse rate (ARR).

In Study 1, 1088 patients were randomized to receive AUBAGIO 7 mg (n=366), AUBAGIO 14 mg (n=359), or placebo (n=363). At entry, patients had an Expanded Disability Status Scale (EDSS) score ≤5.5. Patients had a mean age of 38 years, mean disease duration of 5 years, and mean EDSS at baseline of 2.7. A total of 91% of patients had relapsing remitting multiple sclerosis, and 9% had a progressive form of multiple sclerosis with relapses. The mean duration of treatment was 635, 627, and 631 days for AUBAGIO 7 mg, AUBAGIO 14 mg, and placebo, respectively. The percentage of patients who completed the study treatment period was 75%, 73%, and 71% for AUBAGIO 7 mg, AUBAGIO 14 mg, and placebo, respectively.

There was a statistically significant reduction in ARR for patients who received AUBAGIO 7 mg or AUBAGIO 14 mg, compared to patients who received placebo (see Table 2). There was a consistent reduction of the ARR noted in subgroups defined by sex, age group, prior multiple sclerosis therapy, and baseline disease activity.

There was a statistically significant reduction in the relative risk of disability progression at week 108 sustained for 12 weeks (as measured by at least a 1-point increase from baseline EDSS ≤5.5 or a 0.5 point increase for those with a baseline EDSS >5.5) in the AUBAGIO 14 mg group compared to placebo (see Table 2 and Figure 1).

The effect of AUBAGIO on several magnetic resonance imaging (MRI) variables, including the total lesion volume of T2 and hypointense T1 lesions, was assessed in Study 1. The change in total lesion volume from baseline was significantly lower in the AUBAGIO 7 mg and AUBAGIO 14 mg groups than in the placebo group. Patients in both AUBAGIO groups had significantly fewer gadolinium-enhancing lesions per T1-weighted scan than those in the placebo group (see Table 2).

Study 2 was a double-blind, placebo-controlled clinical trial that evaluated once daily doses of AUBAGIO 7 mg and AUBAGIO 14 mg for up to 40 months in patients with relapsing forms of multiple sclerosis. Patients were required to have a diagnosis of multiple sclerosis exhibiting a relapsing clinical course and to have experienced at least one relapse over the year preceding the trial, or at least two relapses over the two years preceding the trial. Patients were required not to have received any multiple sclerosis medication for at least three months before entering the trial, nor were these medications permitted during the trial. Neurological evaluations were to be performed at screening, every 12 weeks until completion, and after every suspected relapse. The primary end point was the ARR.

A total of 1165 patients received AUBAGIO 7 mg (n=407), AUBAGIO 14 mg (n=370), or placebo (n=388). Patients had a mean age of 38 years, a mean disease duration of 5 years, and a mean EDSS at baseline of 2.7. A total of 98% of patients had relapsing remitting multiple sclerosis, and 2% had a progressive form of multiple sclerosis with relapses. The mean duration of treatment was 552, 567, and 571 days for AUBAGIO 7 mg, AUBAGIO 14 mg, and placebo, respectively. The percentage of patients who completed the study treatment period was 67%, 66%, and 68% for AUBAGIO 7 mg, AUBAGIO 14 mg, and placebo, respectively.

There was a statistically significant reduction in the ARR for patients who received AUBAGIO 7 mg or AUBAGIO 14 mg compared to patients who received placebo (see Table 3). There was a consistent reduction of the ARR noted in subgroups defined by sex, age group, prior multiple sclerosis therapy, and baseline disease activity.

There was a statistically significant reduction in the relative risk of disability progression at week 108 sustained for 12 weeks (as measured by at least a 1-point increase from baseline EDSS ≤5.5 or a 0.5 point increase for those with a baseline EDSS >5.5) in the AUBAGIO 14 mg group compared to placebo (See Table 3 and Figure 2).

Study 3 was a double-blind, placebo-controlled clinical trial that evaluated once daily doses of AUBAGIO 7 mg and AUBAGIO 14 mg for up to 108 weeks in patients with relapsing multiple sclerosis. Patients were required to have had a first clinical event consistent with acute demyelination occurring within 90 days of randomization with 2 or more T2 lesions at least 3 mm in diameter that were characteristic of multiple sclerosis. A total of 614 patients received AUBAGIO 7 mg (n=203), AUBAGIO 14 mg (n=214), or placebo (n=197). Patients had a mean age of 32 years, EDSS at baseline of 1.7, and mean disease duration of two months. The proportion of patients free of relapse was greater in the AUBAGIO 7 mg (70.5%, p <0.05) and AUBAGIO 14 mg (72.2%, p <0.05) groups than in the placebo group (61.7%).

The effect of AUBAGIO on MRI activity was also demonstrated in Study 4, a randomized, double-blind, placebo-controlled clinical trial of multiple sclerosis patients with relapse. In Study 4, MRI was to be performed at baseline, 6 weeks, 12 weeks, 18 weeks, 24 weeks, 30 weeks, and 36 weeks after treatment initiation. A total of 179 patients were randomized to AUBAGIO 7 mg (n=61), AUBAGIO 14 mg (n=57), or placebo (n= 61). Baseline demographics were consistent across treatment groups. The primary endpoint was the average number of unique active lesions/MRI scan during treatment. The mean number of unique active lesions per brain MRI scan during the 36-week treatment period was lower in patients treated with AUBAGIO 7 mg (1.06) and AUBAGIO 14 mg (0.98) as compared to placebo (2.69), the difference being statistically significant for both (p=0.0234 and p=0.0052, respectively).

The 14 mg tablet is pale blue to pastel blue, pentagonal film-coated tablet with dose strength "14" imprinted on one side and engraved with corporate logo on the other side. Each tablet contains 14 mg of teriflunomide.

The 7 mg tablet is very light greenish-bluish grey to pale greenish-blue, hexagonal film-coated tablet with dose strength "7" imprinted on one side and engraved with corporate logo on other side. Each tablet contains 7 mg of teriflunomide.

Inform patients that AUBAGIO may increase liver enzymes and that their liver enzymes will be checked before starting AUBAGIO and for at least 6 months while they are taking AUBAGIO. Advise patients that they should contact their physician if they have any unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine.

Importance of Preventing Pregnancy

Inform patients that based on animal studies, AUBAGIO may cause fetal harm.

Advise females of reproductive potential of the need for effective contraception during AUBAGIO treatment and until completion of an accelerated elimination procedure. Advise them that an accelerated elimination procedure can be used at any time after the discontinuation of AUBAGIO.

Instruct the patient that if she suspects or confirms pregnancy, she should immediately inform her physician.

Instruct men taking AUBAGIO and not wishing to father a child to use effective contraception to minimize any possible risk to the fetus; their female partners should also use effective contraception.

Advise men wishing to father a child to discontinue use of AUBAGIO and undergo an accelerated elimination procedure.

Advise patients that AUBAGIO may stay in the blood for up to 2 years after the last dose and that an accelerated elimination procedure may be used if needed.

Risk of Infections

Inform patients that they may develop a lowering of their white blood cell counts and that their blood counts will be checked before starting AUBAGIO.

Inform patients that they may be more likely to get infections when taking AUBAGIO and that they should contact their physician if they develop symptoms of infection, particularly in case of fever.

Advise patients that the use of some vaccines should be avoided during treatment with AUBAGIO and for at least 6 months after discontinuation.

Serious Allergic Reactions

Advise patients to discontinue AUBAGIO and seek immediate medical attention if any signs or symptoms of a hypersensitivity reaction occur [see Contraindications (4) and Warnings and Precautions (5.5)]. Signs and symptoms include dyspnea, urticaria, and angioedema including lips, eyes, throat, and tongue or skin rash.

Peripheral Neuropathy

Inform patients that they may develop peripheral neuropathy. Advise patients that they should contact their physician if they develop symptoms of peripheral neuropathy, such as numbness or tingling of hands or feet.

Increased Blood Pressure

Inform patients that AUBAGIO may increase blood pressure.

Lactation

Inform patients that it is not known whether this drug is present in human milk. Advise patients, if they are considering breastfeeding, to discuss this with their healthcare provider to decide if they will take AUBAGIO or breastfeed. Advise patients that they should not do both.

Read this Medication Guide before you start using AUBAGIO and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment.

What is the most important information I should know about AUBAGIO?

AUBAGIO may cause serious side effects, including:

Liver problems: AUBAGIO may cause serious liver problems that may lead to death. Your risk of liver problems may be higher if you take other medicines that also affect your liver. Your doctor should do blood tests to check your liver:

within 6 months before you start taking AUBAGIO

1 time a month for 6 months after you start taking AUBAGIO

Call your doctor right away if you have any of the following symptoms of liver problems:

nausea

vomiting

stomach pain

loss of appetite

tiredness

your skin or the whites of your eyes turn yellow

dark urine

Harm to your unborn baby: AUBAGIO may cause harm to your unborn baby. Do not take AUBAGIO if you are pregnant. Do not take AUBAGIO unless you are using effective birth control.

If you are a female, you should have a pregnancy test before you start taking AUBAGIO. Use effective birth control during your treatment with AUBAGIO.

After stopping AUBAGIO, continue using effective birth control until you have blood tests to make sure your blood levels of AUBAGIO are low enough. If you become pregnant while taking AUBAGIO or within 2 years after you stop taking it, tell your doctor right away.

AUBAGIO Pregnancy Registry. If you become pregnant while taking AUBAGIO or during the 2 years after you stop taking AUBAGIO, talk to your doctor about enrolling in the AUBAGIO Pregnancy Registry at 1-800-745-4447, option 2. The purpose of this registry is to collect information about your health and your baby's health.

For men taking AUBAGIO:

If your female partner plans to become pregnant, you should stop taking AUBAGIO and ask your doctor how to quickly lower the levels of AUBAGIO in your blood.

If your female partner does not plan to become pregnant, you and your female partner should use effective birth control during your treatment with AUBAGIO. AUBAGIO remains in your blood after you stop taking it, so continue using effective birth control until AUBAGIO blood levels have been checked and they are low enough.

AUBAGIO may stay in your blood for up to 2 years after you stop taking it. Your doctor can prescribe a medicine to help lower your blood levels of AUBAGIO more quickly. Talk to your doctor if you want more information about this.

What is AUBAGIO?

AUBAGIO is a prescription medicine used to treat relapsing forms of multiple sclerosis (MS). AUBAGIO can decrease the number of MS flare-ups (relapses). AUBAGIO does not cure MS, but it can help slow down the physical problems that MS causes.

It is not known if AUBAGIO is safe and effective in children.

Who should not take AUBAGIO?

Do not take AUBAGIO if you:

have had an allergic reaction to AUBAGIO or a medicine called leflunomide

have severe liver problems

are pregnant or are of childbearing age and not using effective birth control

take a medicine called leflunomide

What should I tell my doctor before taking AUBAGIO?

Before you take AUBAGIO, tell your doctor if you:

have liver or kidney problems

have a fever or infection, or you are unable to fight infections

have numbness or tingling in your hands or feet that is different from your MS symptoms

have diabetes

have had serious skin problems when taking other medicines

have breathing problems

have high blood pressure

are breastfeeding or plan to breastfeed. It is not known if AUBAGIO passes into your breast milk. You and your doctor should decide if you will take AUBAGIO or breastfeed. You should not do both..

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Using AUBAGIO and other medicines may affect each other causing serious side effects. AUBAGIO may affect the way other medicines work, and other medicines may affect how AUBAGIO works.

Especially tell your doctor if you take medicines that could raise your chance of getting infections, including medicines used to treat cancer or to control your immune system.

Ask your doctor or pharmacist for a list of these medicines if you are not sure.

Know the medicines you take. Keep a list of them to show your doctor or pharmacist when you get a new medicine.

decreases in your white blood cell count. Your white blood cell counts should be checked before you start taking AUBAGIO. When you have a low white blood cell count you:

may have more frequent infections. You should have a skin test for TB (tuberculosis) before you start taking AUBAGIO. Tell your doctor if you have any of these symptoms of an infection:

fever

tiredness

body aches

chills

nausea

vomiting

should not receive certain vaccinations during your treatment with AUBAGIO and for 6 months after your treatment with AUBAGIO ends.

numbness or tingling in your hands or feet that is different from your MS symptoms. You have a greater chance of getting peripheral neuropathy if you:

are over 60 years of age

take certain medicines that affect your nervous system

have diabetes

Tell your doctor if you have numbness or tingling in your hands or feet that is different from your MS.

Allergic reactions, including serious skin problems. Tell your doctor if you have difficulty breathing, itching, swelling on any part of your body including in your lips, eyes, throat or tongue, or any skin problems such as rash or redness and peeling.

new or worsening breathing problems. Tell your doctor if you have shortness of breath or coughing with or without fever.

high blood pressure. Your doctor should check your blood pressure before you start taking AUBAGIO and while you are taking AUBAGIO.

The most common side effects of AUBAGIO include:

headache

diarrhea

nausea

hair thinning or loss (alopecia)

increases in the results of blood tests to check your liver function

Tell your doctor if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of AUBAGIO. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-332-1088.

How should I store AUBAGIO?

Store AUBAGIO at room temperature between 68°F to 77°F (20°C to 25°C).

Keep AUBAGIO and all medicines out of reach of children.

General information about the safe and effective use of AUBAGIO.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use AUBAGIO for a condition for which it was not prescribed. Do not give AUBAGIO to other people, even if they have the same symptoms you have. It may harm them.

This Medication Guide summarizes the most important information about AUBAGIO. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about AUBAGIO that is written for healthcare professionals.

For more information, go to www.aubagio.com or call Genzyme Medical Information Services at 1-800-745-4447, option 2.

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